Some 1,2,4-triazolo[1,5-a]triazines are known to the art. Certain 1,2,4-triazolo[1,5-a]triazines are disclosed as being pharmaceuticals, and some are said to be bronchodilators. In the patents discussed below, some of the compounds which are triazolo[1,5-a]triazines are referred to therein as triazolo[2,3-a]triazines.
East German Patent No. 205,905 discloses substituted 1,2,4-triazolo[2,3-a]triazines which are prepared by reacting a 5-amino-1,2,4-triazole-1-thiocarboxamide with an orthoester to provide compounds which are substituted at ring position 2 by thioalkyl or (un)substituted thiobenzyl; position 5 by thio; position 6 by alkyl, (un)substituted benzyl or aryl; and position 7 by (un)substituted alkyl.
European Patent Appln. No. 122,978 discloses 1,2,4-triazolo[1,5-a]triazines optionally substituted in the 2-position by hydrogen or methyl; in the 5-position by hydroxy or amino; and in the 7-position by hydrogen, thio, hydroxy, alkythio or amino. These compounds are claimed to have gastric acid secretion reducing activity.
The following related articles disclose the syntheses of certain 1,2,4-triazolo[1,5-a]triazines.
E. Taylor and R. Hendess, J. Am. Chem. Soc., 87 1980 (1965), disclose triazolo[2,3-a]triazines, the unsubstituted parent system with oxygen at position 5(5-azahypozanthine) or amino at position 5. These were synthesized as potential purine antagonists.
R. Bokladere and V. Grinshtein, Chemistry of Heterocyclic Compounds (originally published in Khimiya Geterotsiklicheskikh Soidinenii), 6, 522-523 (1970), report the syntheses of various 5-amino-1,2,4-triazolo[1,5-a]triazines by cyclization of 3-amino-2-guanyltriazoles with triethyl orthoformate or formic acid. These compounds were substituted by alkyl or phenyl in the 2-position and optionally by amino in the 7-position. R. Bokladere and A. Liepin, Chemistry of Heterocyclic Compounds, 9, 256-260 (1973), report their study of the reaction of 3-aminotriazoles with carbethoxyisothiocyanate, and subsequent cyclizations to give 1,2,4-triazolo[1,5-a]triazines substituted in the 5 and 7-positions by oxygen or sulfur. R. Bokladere et al., Chemistry of Heterocyclic Compounds, 9, 388-391 (1973), describe the preparation of 7-methylthiotriazolo[1,5-a]triazines by alkylation of triazolylthioureas with iodomethane, and subsequent cyclization with triethyl orthoformate.
L. Capuano and H. Schrepfer, Chem. Ber., 104, 3039-3047 (1971), disclose 1,2,4-triazolo[1,5-a]triazines substituted by oxo in the 5-position; thio in the 7-position; and hydrogen or methyl in the 8-position.
T. Hirata et al., J. Heterocycl. Chem., 9, 99 (1972), describe some reactions of 3-amino-1,2,4-triazole with isocyanates and isothiocyanates, and subsequent cyclizations to 1,2,4-triazolo[1,5-a]triazines having an oxo or a thio substituent in the 5-position.
S. Langdon et al., J. Chem. Soc., 993-998 (1984), disclose 1,2,4-triazolo[1,5-a]triazines substituted by (un)substituted phenyl in the 2-position; and either dimethylamino in both 5- and 7-positions or morpholino in both the 5- and 7-positions.
J. Svetlik, Heterocycles, 20, 1495-9 (1983), discloses 1,2,4-triazolo[1',5':1,2]-1,3,5-triazino[5,6-a]-benzimidazole, but not the triazolo[1,5-a]triazines as such.
J. Kobe et al., Monatsh. Chem., 97, 713-22 (1966), disclose the synthesis of substituted triazolo[4,3-a]triazines. Subsequently, J. Kobe et al., Tetrahedron, 26, 3357-3368 (1970), disclose 1,2,4-triazolo[2,3-a]triazines as isomeric products formed on rearrangement of the corresponding products of the [4,3-a]series.
R. Deshpande and A. Rama Rao, Synthesis, 863-865 (1974), disclose the synthesis of 3-alkyl and 3-aryl triazolo[4,3-a]triazines from acyl derivatives of symmetrically substituted 2-hydrazino-3-triazines. These compounds, which contained a substituted amino moiety such as morpholino in the 5- and 7-positions, were subsequently isomerized to the corresponding triazolo[2,3-a]triazines.
Bronchodilator triazolo[1,5-c]pyrimizines substituted by a cyclic amino moiety are known. For example, U.S. Pat. No. 4,572,910 discloses substituted triazolo[1,5-c]pyrimidines which differ from triazolo[1,5-a]triazines in that N replaces C at ring position 8. These compounds are substituted on the pyrimidine ring in position 5 and/or 7 by a cyclic amino group such as piperidino, piperazino, morpholino or thiomorpholino bonded through the nitrogen atom to the pyrimidine ring. These compounds may also contain alkyl in the 5-position.